Recent advances in cancer treatment have largely bypassed ovarian cancer, and the standard-of-care has changed very little in the last two decades. Yet the biology of ovarian cancer affords tremendous opportunity for innovation. The vast majority of ovarian cancers uniquely express the a isoform of folate receptor (FRA). This makes FRA an ideal target for radioimmunotherapy (RAIT), which involves the parenteral administration of radiolabeled antitumor ligands. Unfortunately, dose-limiting radiotoxicity has limited the ability of RAIT to induce significant clinical responses. Our HotDot radiolabel is a compact cluster of radioactive atoms that can be easily attached to biological molecules such as antibodies. HotDot radiolabeling will enable antitumor ligands to deliver more radioactivity per target antigen, which will increase the fraction of the administered activity that can be retained by the tumor. This will have the dual benefits of higher efficacy and a better safety profile, dramatically improving the therapeutic index of RAIT. The objective of the proposed work is to test the hypothesis that a b-emitting 188Re HotDot targeted to FRA can selectively and safely deliver therapeutic radioactivity to peritoneal tumors. Such a compound could become a viable treatment for platinum-resistant ovarian cancer. Aim 1 will focus on preparing 188Re HotDot conjugates with folic acid. The performance of these conjugates will be tested in live cell binding assays to determine optimal formulations to evaluate in vivo. Aim 2 will evaluate the dosimetry of the most promising conjugate in a relevant animal model. Ideally, the proposed research will lead to a novel compound that can be taken forward to preclinical therapy studies and ultimately an IND application. PUBLIC HEALTH RELEVANCE: Patients diagnosed with ovarian cancer have little hope for complete remission, and the currently available treatments are physically and emotionally devastating. This project seeks to develop an innovative radiotherapy for ovarian cancer that can prolong survival and concomitantly improve patient quality of life.